Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients
Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (<i>SMN1</i>) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense olig...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-04-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/9/4329 |
| _version_ | 1797536870781943808 |
|---|---|
| author | Laura Bianchi Maria Sframeli Lorenza Vantaggiato Gian Luca Vita Annamaria Ciranni Francesca Polito Rosaria Oteri Eloisa Gitto Fabrizio Di Giuseppe Stefania Angelucci Antonio Versaci Sonia Messina Giuseppe Vita Luca Bini M’hammed Aguennouz |
| author_facet | Laura Bianchi Maria Sframeli Lorenza Vantaggiato Gian Luca Vita Annamaria Ciranni Francesca Polito Rosaria Oteri Eloisa Gitto Fabrizio Di Giuseppe Stefania Angelucci Antonio Versaci Sonia Messina Giuseppe Vita Luca Bini M’hammed Aguennouz |
| author_sort | Laura Bianchi |
| collection | DOAJ |
| description | Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (<i>SMN1</i>) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support <i>SMN</i> improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression. |
| first_indexed | 2024-03-10T12:06:59Z |
| format | Article |
| id | doaj.art-b94b06eb138b4972bc2775772eeb26e3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:06:59Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b94b06eb138b4972bc2775772eeb26e32023-11-21T16:31:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01229432910.3390/ijms22094329Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 PatientsLaura Bianchi0Maria Sframeli1Lorenza Vantaggiato2Gian Luca Vita3Annamaria Ciranni4Francesca Polito5Rosaria Oteri6Eloisa Gitto7Fabrizio Di Giuseppe8Stefania Angelucci9Antonio Versaci10Sonia Messina11Giuseppe Vita12Luca Bini13M’hammed Aguennouz14Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, 53100 Siena, ItalyNemo Sud Clinical Centre, 98125 Messina, ItalyFunctional Proteomics Laboratory, Department of Life Sciences, University of Siena, 53100 Siena, ItalyNemo Sud Clinical Centre, 98125 Messina, ItalyUnit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, ItalyUnit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, ItalyUnit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, ItalyNeonatal and Paediatric Intensive Care Unit, Department of Human Pathology in Adult and Developmental Age, University of Messina, 98125 Messina, ItalyDentistry and Biotechnology, and Proteomics Unit, Centre of Advanced Studies and Technoloy, Department Medical, Oral & Biotechnological Sciences, “G. d’Annunzio”, University of Chieti-Pescara, 66100 Chieti, ItalyDentistry and Biotechnology, and Proteomics Unit, Centre of Advanced Studies and Technoloy, Department Medical, Oral & Biotechnological Sciences, “G. d’Annunzio”, University of Chieti-Pescara, 66100 Chieti, ItalyIntensive Care Unit, AOU Policlinico “G. Martino”, 98125 Messina, ItalyUnit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, ItalyNemo Sud Clinical Centre, 98125 Messina, ItalyFunctional Proteomics Laboratory, Department of Life Sciences, University of Siena, 53100 Siena, ItalyUnit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, ItalySpinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (<i>SMN1</i>) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support <i>SMN</i> improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression.https://www.mdpi.com/1422-0067/22/9/4329neuromuscular diseasespinal muscular atrophy type 1nusinersenASOapolipoprotein A1apolipoprotein E |
| spellingShingle | Laura Bianchi Maria Sframeli Lorenza Vantaggiato Gian Luca Vita Annamaria Ciranni Francesca Polito Rosaria Oteri Eloisa Gitto Fabrizio Di Giuseppe Stefania Angelucci Antonio Versaci Sonia Messina Giuseppe Vita Luca Bini M’hammed Aguennouz Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients International Journal of Molecular Sciences neuromuscular disease spinal muscular atrophy type 1 nusinersen ASO apolipoprotein A1 apolipoprotein E |
| title | Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients |
| title_full | Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients |
| title_fullStr | Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients |
| title_full_unstemmed | Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients |
| title_short | Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients |
| title_sort | nusinersen modulates proteomics profiles of cerebrospinal fluid in spinal muscular atrophy type 1 patients |
| topic | neuromuscular disease spinal muscular atrophy type 1 nusinersen ASO apolipoprotein A1 apolipoprotein E |
| url | https://www.mdpi.com/1422-0067/22/9/4329 |
| work_keys_str_mv | AT laurabianchi nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT mariasframeli nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT lorenzavantaggiato nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT gianlucavita nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT annamariaciranni nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT francescapolito nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT rosariaoteri nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT eloisagitto nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT fabriziodigiuseppe nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT stefaniaangelucci nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT antonioversaci nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT soniamessina nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT giuseppevita nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT lucabini nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients AT mhammedaguennouz nusinersenmodulatesproteomicsprofilesofcerebrospinalfluidinspinalmuscularatrophytype1patients |